Objective: Delirium is a frequent complication after surgery with important negative outcomes for affected patients and society. However, it is still largely unknown why some patients have a predisposition for delirium and others not. To increase our understanding of the neural substrate of postoperative delirium, we studied the association between preoperative brain MRI features and the occurrence of delirium after major surgery. Methods: A group of 413 patients without dementia (Mean 72 years, SD: 5) was included in a prospective observational two-center study design. The study was conducted at Charité Universitätsmedizin (Berlin, Germany) and the University Medical Center Utrecht (Utrecht, The Netherlands). We measured preoperative brain volumes (total brain, gray matter, white matter), white matter hyperintensity volume and shape, brain infarcts and cerebral perfusion, and used logistic regression analysis adjusted for age, sex, intracranial volume, study center and type of surgery. Results: Postoperative delirium was present in a total of 70 patients (17%). Preoperative cortical brain infarcts increased the risk of postoperative delirium, although this did not reach statistical significance (OR (95%CI): 1.63 (0.84–3.18). Furthermore, we found a trend for an association of a more complex shape of white matter hyperintensities with occurrence of postoperative delirium (OR (95%CI): 0.97 (0.95–1.00)). Preoperative brain volumes, white matter hyperintensity volume, and cerebral perfusion were not associated with occurrence of postoperative delirium. Conclusion: Our study suggests that patients with preoperative cortical brain infarcts and those with a more complex white matter hyperintensity shape may have a predisposition for developing delirium after major surgery.